Opioids provide analgesia trough binding to μ-opioid receptors in the central nervous system (CNS). In addition to acting centrally, opioid agonists also act peripherally, e.g. in the GI-tract through binding to opioid receptors in the enteric nervous system (ENS) leading to disruption of bowel motility and causing a variety of deleterious effects including delayed intestinal transit time, decreased peristalsis, increased water reabsorption, and decreased gastrointestinal secretions.
Peripheral opioid-mediated GI side effects occur frequently and can limit the utility of opioids. The peripheral deleterious effects of opioids give rise to a variety of GI symptoms often referred to as opioid-induced bowel dysfunction (OBD). The most frequent and often most bothersome symptom is opioid-induced constipation (OIC), which occurs in a substantial proportion of patients with incidences ranging from 15-90%. In addition to OIC, other OBD symptoms may include abdominal bloating, discomfort and pain, feeling the need to have a bowel movement (BM) but unable to, straining, rectal pain and flatulence, among others.
In contrast to central opioid-related adverse effects which typically lessen over time, GI symptoms associated with chronic opioid use are not prone to tolerance. Thus, symptoms can persist for the duration of opioid management. This can result in important clinical consequences including increased risk for faecal incontinence, faecal impaction/bowel obstruction, bowel perforation, haemorrhoids, anal fissure, pelvic organ prolapse, pain management interruptions, as well as poor quality of life, poor workplace productivity, and increased healthcare utilization.
Current first-line therapy for OIC often centres on stool softeners and laxatives, such as bulking agents and bowel stimulants, diet and exercise, and opioid dose reduction, switching or discontinuation. However, these treatments are not directed at the primary aetiology of OIC and are often marginally or completely ineffective. Less than half of patients on opioid therapy achieve sufficient effect from related laxatives. Furthermore, these treatments may be burdensome to patients, are often associated with many side effects and may ultimately compromise pain management. In addition, two peripherally acting μ-opioid receptor antagonists have been approved in the EU and the US for use in chronic pain patients for the treatment of OIC: Movantig® (naloxegol), an oral tablet, and Relistor® (methylnaltrexone bromide), administered subcutaneously (Relistor® [methylnaltrexone], UK SmPC, January 2016; Movantig® [naloxegol], German SmPC, December 2014).
Historical experience with oral naloxone formulations for the treatment of OIC or as an additional abuse deterrent property within fixed-dose combination (FDC) products has been extensive (e.g., Valoron® N, Valoron® N retard, Suboxone®, Targin®/Targinact®/Targiniq™). NLX PR Tablets have very low systemic availability due to high first pass metabolism (<3%) and maximum free plasma concentrations are substantially below the μ-opioid receptor inhibition constant (Ki).
Naloxone is the semi-synthetic N-alkyl derivative of oxymorphone and a specific opioid antagonist which has no agonistic or morphine-like properties characteristic of other narcotic antagonists (e.g., nalorphine, levallorphan).
Naloxone acts by competitively binding to opioid receptors. It binds most strongly to the receptor, but shows also antagonistic activity at the κ- and δ-receptors. Since naloxone displays antagonistic activity at all opioid receptors, albeit with widely different affinities, and is devoid of any agonistic actions, it does not cause respiratory depression, even in excessive doses or in the absence of morphine intoxication.
Under normal circumstances, naloxone has no or only few pharmacological effects unless opioids with agonistic activity have been administered previously.
Naloxone is a suitable opioid antagonist for the treatment of opioid-induced constipation. Naloxone is rapidly and completely absorbed after oral administration and because the substance is subject to extensive first-pass metabolism, only small amounts of unmetabolised naloxone are available to the system. The vast majority of the applied substance is found in blood in the form of inactive or only mildly active metabolites such as naloxone-3-glucuronide or beta-6-naloxol. In suitable doses, naloxone is an ideal candidate for remedying opioid-induced constipation: in the intestine it is present as an active substance and can thus counter the paralysing effect of the opioid on the gastrointestinal tract, while after absorption it is largely metabolised during the first passage in the liver, and thereby becomes inactive. The analgesic effect of the opioids is thus not affected.
Since the paralysis does not only affect the duodenum and the upper part of the small intestine, but the entire gastrointestinal tract, the opioid-induced constipation cannot be treated successfully with a composition that releases the naloxone rapidly. WO 2011/117306 discloses a two-layer tablet, which in one layer contains an opioid agonist, and in another layer an opioid antagonist, wherein the tablet quickly releases both active substances. The advantage of this double-layer is to suppress the side effects of the opioid agonist, but it does not focus on suppression of the opioid-induced constipation.
The combined preparation Targin® is available on the market and comprises a mixture of the opioid agonist oxycodone in the form of a hydrochloric salt, and the opioid antagonist naloxone also in the form of a hydrochloric salt. In this preparation, the active substances are released in a prolonged manner. It is therefore suitable for the parallel treatment of pain and opioid-induced constipation. However, this monolithic formulation has the disadvantage that the release rates of the two active substances are fixed. Individualised treatments are therefore difficult to optimise.
In addition, infusion solutions available on the market for the treatment of opioid poisoning are only naloxone combined preparations, in which naloxone and the opiate are present in a fixed proportion to each other. However, for the treatment of opioid-induced constipation, it would be desirable to have single agent naloxone preparations, since this would allow administering naloxone both independently of the nature of the opiate and in variable doses. The desired quantity of naloxone could therefore be applied, which would lead to an optimal treatment. Naloxone single agent preparations are described in the patent literature, such as in WO 98/25613 A2. However, the release of naloxone from these compositions is dependent on the ambient pH in the gastrointestinal tract. A uniform application of naloxone to the entire gastrointestinal tract, and therefore an optimal treatment, are thus not possible with such products.
Naloxone has been used for many decades in millions of patients as solution for injection for the complete or partial reversal of opioid effects and for the diagnosis of suspected acute opioid overdosage. Furthermore, in combination with tilidine, naloxone for oral administration is marketed since more than 35 years in Germany for the treatment of severe pain without limitation of duration of use (Valoron® N, German SmPC, December 2014). In addition, an oral FDC product containing oxycodone and naloxone (Targin®, Targinact®) indicated for patients with moderate-to-severe pain is marketed within the EU since 10 years. Thus, due to its wide clinical use, the pharmacodynamic, pharmacokinetic and toxicological properties of naloxone are well known.
The non-clinical pharmacology and toxicology of naloxone (oral and parenteral) has been well characterised with much of the information available in the published literature and regulatory reviews of recently approved products containing naloxone as an oral prolonged-release formulation (e.g., Valoron® N, Tagin®/Targinact®/Targiniq™).
Yet, there is still a need to adapt and optimize dosage regimens for patients suffering from opioid induced constipation. So far fixed dosage combination of oxycodone/naloxone (e.g. Targin) have been used.